ABSTRACT Gliomas remain among the most intractable problems in oncology. These tumors can be differentiated into 2 distinct subsetsbasedongeneticprofile.ThoseharboringmutationsinIsocitrateDehydrogenase1or2(IDH1/2)tendtooccur in younger patients and follow a progression from slow growing, indolent tumors (low-?grade), to rapidly proliferating high-?grade tumors. The IDH gain-?of-?function mutations catalyze the reduction of ?-?ketoglutarate (?KG) to 2-? hydroxyglutarate (2HG), an oncometabolite that accumulates in millimolar concentrations in the tumor cell. 2HG has beenshowntodrivethemalignantphenotypeinawidevarietyofcancersthatharborIDH1/2mutations.Thepresence of these mutations in the earliest grade of glioma suggests that dependence on IDH may be during the indolent phase, prior to transformation to higher grade, which is characterized by an accrual of multiple tumor suppressor and oncogenic mutations that are powerful drivers of tumor proliferation. Adding support to this idea, we have demonstrated that despite low proliferative rates, the low-?grade gliomas are highly metabolically active. We used 13C-? NMR in vivo in patients with IDH-?mutated gliomas to determine the activity of metabolic pathways in low-? and high-? grade disease. Across the spectrum, we observed robust labeling of citric acid cycle intermediates and the 2HG pool from both substrates, a finding that is particularly striking for the low-?grade gliomas and suggests that the metabolic state is independent of the proliferative state. Emerging phase 1 glioma clinical trial data from treatment with the selectiveIDH1inhibitor,AG-?120(AgiosPharmaceuticals),showsthattreatmentofprogressivelow-?gradegliomas,before radiographic progression to high-?grade disease, is associated with prolonged stable disease. This is in marked contrast withrapidprogressioninpatientswithrecurrenthigh-?gradegliomastreatedwiththeinhibitor.Thequestionremainsas to what the mechanism of stable disease is in the low-?grade subgroup and whether treatment at an even earlier stage (prior to progression in the stable phase) is the optimal time for achieving a response. We hypothesize that low-?grade gliomas, during the long period of stable disease prior to further transformation, are highly metabolically active with multiplesubstratescontributingtothedynamicregulationofthe2HGpoolandinthisstatearedependentonsustained productionof2HG.Furthermore,wehypothesizethatfollowingprogressiontohigh-?gradediseasesustainedproduction of2HGisnolongeressentialtotumorgrowth.Totestthesehypotheses,wehave3SpecificAims: 1)Toinvestigatethe cellular, molecular, and metabolic consequences of IDH1 inhibition in patients with low grade glioma with the goal of determining whether IDH is a driver mutation in the setting of very low tumor cell proliferation; 2) To determine whether high grade glioma progression on an IDH inhibitor is due to intrinsic or acquired resistance and assess the impact of IDH inhibition in the setting of radiation and/or chemotherapy using clinically validated IDH mutant patient derived xenograft mouse models; and 3) To dynamically image metabolic processes in vivo and develop biomarkers of IDH response/lack of response. The impact of these studies will be directly translatable to clinical trials and clinical managementofIDH-?mutantgliomasforwhichimprovedtherapeuticsaredesperatelyneeded.